Gastrointestinal Leiomyosarcoma Research Articles

Abstract 3100: XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization

Abstract STS constitutes a family of rare mesenchymal tumors with more than 70 subtypes described. The limited treatment options available for advanced STS patients underline the need for reliable preclinical models to test new therapeutic approaches. We established a panel of PDX models (XenoSarc) by subcutaneous implantation of fresh tumor specimens in athymic mice (nu/nu NRMI). Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of animals. At each passage tumor fragments were collected for histopathological and molecular characterization. In an ongoing effort 493 STS samples from 414 consenting patients treated at the University Hospitals, Leuven (Belgium) have been transplanted. A total of 67 PDX models from 20 STS subtypes have been established, meaning they have stable morphological, immunohistochemical and genetic characteristics over at least 2 passages. The PDX platform includes more common STS subtypes such as myxofibrosarcoma (n=12 models), gastrointestinal stromal tumors (9), dedifferentiated liposarcoma (10), and leiomyosarcoma (8), as well as models from ultra-rare subtypes, e.g. pulmonary intimal sarcoma, extraskeletal osteosarcoma, mesenchymal chondrosarcoma, myxoinflammatory fibroblastic sarcoma and others. All relevant details about the donor patient and tumor characteristics, including sensitivity to the standard treatments, are known for every model. The models are well-characterized, with availability of molecular information on genomic profile (by low-coverage whole genome sequencing), and expression profile (by RNA sequencing). Xenografts are accompanied by ready to use tissue microarrays (TMA) from the models, which can be exploited for target identification and model selection for preclinical studies. Ex-mouse material can also be used to establish primary cell cultures and 3D organoids for in vitro screening purposes. The XenoSarc platform offers opportunities for studying the biology of various sarcoma subtypes including ultra-rare entities and was found to be a very reliable tool for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is available for collaborative preclinical projects with academic and industrial partners. Citation Format: Agnieszka Wozniak, Luna De Sutter, Lore De Cock, Britt Van Renterghem, Che-Jui Lee, Yannick Wang, Ulla Vanleeuw, Kimberly Verbeeck, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Joris Jaekers, Dirk Van Raemdonck, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3100.

Minimally Invasive Endoscopic Treatment of Gastric Leiomyosarcoma: A Rare Case Report and Review of Literature

Background Since the c-kit was described in 1998, gastrointestinal LMS remains a relatively rare disease in the post-GIST era. Previous studies have reported that gastric LMS accounts for only 1% of gastric tumors. This report provides valuable endoscopic and endoscopic ultrasound data for rare diseases such as primary gastric leiomyosarcoma, which can add experience for clinical diagnosis to the current literature. Particularly, this case proved that the early-stage lesions can be treated with minimally invasive endoscopic treatment with high safety, good tolerance, and satisfactory clinical results. Case Presentation A 63-year-old female patient visited our hospital mainly because of “epigastric pain and discomfort for 2 months.” After hospitalization, the relevant examinations were performed, and laboratory examination showed no obvious abnormalities. Abdominal contrast-enhanced CT found slight thickening of the gastric body wall. Ultrasonic gastroscopy revealed a round protuberant mass that originated from the muscularis mucosa on the great curvature of the gastric body, with a largest diameter of 16 mm. After full communication with the patient and exclusion of contraindications, the patient successfully underwent diagnostic endoscopic submucosal dissection (ESD) surgery. The postoperative pathological findings, immunohistochemical staining panel and molecular detection all improved that the mass was leiomyosarcoma. After 18 months of follow-up, the patient was in good condition, and there was no relapse on gastroscopy and abdominal enhanced CT. Conclusion Gastrointestinal leiomyosarcoma can be successfully resected by minimally invasive endoscopic treatment with high safety, good tolerance, and satisfactory clinical results. This shows that ESD is an effective method for the treatment of these diseases and has promising prospects for clinical application.

Leiomyosarcoma of Recto Sigmoid Colon: A Rare Case Report

Leiomyosarcoma (LMS) of sigmoid colon is extremely rare high grade neoplasm with poor prognosis. Gastrointestinal leiomyosarcoma are aggressive mesenchymal tumors. Here we present an unusual case of leiomyosarcoma of sigmoid colon with adhesions and perforation in small intestine. Case presentation: A 65 years old male patient referred to our institute with complaints of vomiting, pain and distention of abdomen .Clinical examination showed rigidity and guarding of abdomen with diminished bowel sounds. Clinically diagnosed as intestinal obstruction. Colonoscopy revealed growth at recto-sigmoid junction. Histopathology of biopsy reported with differential diagnosis. Malignant gastrointestinal stromal tumors (GIST) and Leiomyosarcoma. Immunohistochemistry confirmed the final diagnosis. SMA positive and CD117 negative. Hence diagnosed as leiomyosarcoma of rectosigmoid colon. Conclusion: Colonic leiomyosarcoma is rare and its occurrence in rectosigmoid colon is unusual. Leiomyosarcoma can be differentiated from GIST by IHC marker.

Prognostic Factors in Gastrointestinal Leiomyosarcomas: An Analysis Using the Surveillance, Epidemiology, and End Results (SEER) Database.

BackgroundGastrointestinal leiomyosarcomas (LMSs) from intramural smooth muscle are extremely rare, with limited literature. This paper evaluates the epidemiology and survival and prognostic factors in LMSs of the gastrointestinal tract.MethodsClinical data from the Surveillance, Epidemiology and End Results (SEER) 18 registry from 2001 to 2016 with additional treatment fields were compared between primary tumor sites using the chi-squared test for categorical variables and ANOVA for continuous variables. A five-year survival rate analysis was performed for overall and cancer-specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox proportional models using the variables age group, tumor location, grade, stage, surgery, and chemotherapy.ResultsWe identified a total of 523 patients diagnosed with LMSs of the gastrointestinal tract. The median age of diagnosis was 66 years, with no significant difference between tumor sites for age, sex, and race. The five-year overall survival was 77.3%, and the cancer-specific survival was 90.3%. In the multivariate analysis, grade and stage of tumor were the only factors significantly affecting survival in this cohort.ConclusionWhile surgical status significantly affected survival in the univariate analysis, when adjusted for other factors, the HR for death was not significantly different by surgical therapy. Grade 3 tumors and tumors with distant metastasis at diagnosis were associated with worse survival among these patients.

Two cases of primary leiomyosarcoma of sigmoid colon treated with laparoscopic surgery: A case report and a review of literature.

Introduction and importanceLeiomyosarcoma (LMS) of the colon is an extremely rare and highly invasive tumor arising from the muscularis propria of the gastrointestinal tract. After the introduction of oncogenic role of KIT by immunohistochemistry (IHC), the reported cases of gastrointestinal leiomyosarcoma were highly limited. True LMS of the colon is such a rare disorder that there isn't much description of its nature.Case presentationWe reported two very rare cases of primary leiomyosarcoma of sigmoid colon, which referred to our institution with symptoms of abdominal pain, lower GI bleeding and fatigue. After the initial investigations, both patients were diagnosed with primary LMS of sigmoid colon that underwent laparoscopic tumor resection.Clinical discussionThe classical colonic LMS presents with a vast majority of non-specific symptoms including mild abdominal pain, fresh/obscure rectal bleeding, and weight loss. The most common location for colonic LMS is the sigmoid colon, and ascending colon. The prognostic factors for the disease outcome have not been established properly; however, patient age, tumor size/grade, and local/distant dissemination are of great importance.ConclusionHerein, we reported two rare cases of primary leiomyosarcoma of sigmoid colon that was treated with laparoscopic surgery.

Laparoscopic and endoscopic cooperative surgery for leiomyosarcoma of the stomach: a case report with a review of the literature

BackgroundLeiomyosarcoma is a rare tumor that could originate from the gastrointestinal tract, uterus, kidney, retroperitoneum, and the soft tissues of the extremities. It accounts for only 1% of all gastrointestinal mesenchymal tumors and primary leiomyosarcoma of the stomach is extremely rare. Most cases reported as leiomyosarcoma of the stomach before the development of KIT immunohistochemistry might be gastrointestinal stromal tumors (GISTs) of the stomach and only 18 cases of leiomyosarcoma of the stomach have been reported since early 2000s. We report here a patient with leiomyosarcoma of the stomach treated by laparoscopic and endoscopic cooperative surgery (LECS).Case presentationA 59-year-old man was referred to our hospital for an early gastric cancer, which was initially treated by endoscopic submucosal dissection. Six months after his initial treatment, a follow-up esophagogastroduodenoscopy revealed a small polypoid lesion at the lesser curvature of the proximal stomach, which appeared to be a hyperplastic polyp. However, one and a half years later, the lesion grew and showed more irregular surface. Biopsy at the time revealed smooth muscle cell proliferation suggestive of leiomyoma. Three years later, the lesion grew even larger and biopsy showed pleomorphic spindle cells. Immunohistochemical study showed positive staining for alpha-smooth muscle actin and desmin, but negative for c-kit and CD34. Ki-67 labeling index was nearly 60%. Based on these findings, the diagnosis of leiomyosarcoma was established. The patient subsequently underwent a partial gastrectomy by LECS. The patient is currently in good condition without recurrence or metastasis at 12 months after surgery.ConclusionsLeiomyosarcoma of the stomach is extremely rare. This is the first report of leiomyosarcoma of the stomach treated by LECS. We could also follow its appearance change through endoscopic examination for 3 years.

Gastrointestinal leiomyosarcoma demonstrate a predilection for distant recurrence and poor response to systemic treatments

BackgroundPrimary leiomyosarcoma (LMS) of the gastrointestinal (GI) tract is rare. Limited literature exists regarding the clinical characteristics and outcome for patients with localised and metastatic disease. MethodsA retrospective chart review was performed for patients greater than 18 years of age diagnosed with GI LMS at The Royal Marsden Hospital between 1 January 2000–1 May 2020. Descriptive statistics were performed. Patients were censored at data cut-off date of 27 June 2020. ResultsForty-six patients with a median age at diagnosis of 54 years (range 25–85) were identified. Fifteen percent (n = 7) of patients previously received abdominal radiation for an unrelated cancer. All patients with localised disease (n = 36) had resection with oncological margins. For patients who underwent potentially curative surgery, median recurrence-free survival (mRFS) was 13 months (0.4–183 months), and half of these patients (n = 18) developed recurrent disease post resection (distant n = 16, local n = 2). Median overall survival (mOS) was 27 months for patients with distant recurrence. Twenty-one percent (n = 10) of patients presented with synchronous metastatic disease and their mOS was 19 months. Median progression-free survival (mPFS) for patients treated with conventional chemotherapy ranged from 2.0 to 8.0 months. ConclusionThe risk of recurrence is significant, and recurrence-free survival was short even with complete oncologic resection. The relationship of prior abdominal radiotherapy to the development of GI LMS warrants further investigation. Outcomes with systemic therapy for metastatic disease were poor and there is a need for the development of more effective systemic therapies.

Leiomyosarcoma of the transverse colon with lymph node metastasis and malignant transformation: a case report

BackgroundThe concept of GIST was established in 1998, clearly differentiating between gastrointestinal leiomyosarcoma and GISTs among gastrointestinal mesenchymal tumors. Lymph node metastasis is extremely rare in true gastrointestinal leiomyosarcoma, and there are no reports of malignant transformation from leiomyoma.Case presentationThe patient was an old woman who had undergone endoscopic mucosal resection for an Is polyp on the left side of the transverse colon at the age of 73. She was diagnosed with leiomyoma with positive surgical margins. Subsequently, she presented to our institution with a sensation of pressure in the upper abdominal region as a chief complaint at the age of 76 years. Abdominal computed tomography and colorectal endoscopy showed a tumor lesion with invagination of the intestines in the transverse colon, the same site as that of the previously resected leiomyoma. A biopsy suggested a smooth muscle tumor, and we performed partial left transverse colectomy and lymph node dissection under a diagnosis of recurrence and enlargement of the previously incompletely resected leiomyoma. Histopathological examination revealed spindle-shaped tumor cells, and the mitotic activity was 30–40/10 high-power field. Tumor cells were immunohistologically positive for α-smooth muscle actin and h-caldesmon; partially positive for desmin; negative for c-kit, CD34, DOG-1, and the S-100 protein; and showed a Ki-67 labeling index of 70–80%. She was diagnosed with leiomyosarcoma malignantly transformed from leiomyoma. Metastasis was found in 1 of the 14 resected lymph nodes. The patient did not undergo adjuvant chemotherapy, but has survived with no recurrence at 2 years after the surgery.ConclusionsWe have reported a case of leiomyosarcoma of the transverse colon with lymph node metastasis that was malignantly transformed from a leiomyoma.

Gastric leiomyosarcoma in a 3-year-old boy

Abstract A 3-year-old boy presented with anemia and a palpable abdominal tumor. The operative finding was a 10.5×9.6×4.6-cm tumor that infiltrated the anterior wall of the stomach. Local excision was performed. The tumor was histopathologically diagnosed as leiomyosarcoma with immunoreactivity for alpha-smooth muscle actin and muscle actin, but not for CD34, c-kit, and S-100. The tumor was characterized as highly malignant because of its size, high mitotic count, nuclear atypia, and high MIB-1 labeling index. After 6 months of follow-up, recurrence developed in the remnant stomach and liver metastasis was observed. Partial gastrectomy and lateral segment resection of the liver were performed. Subsequently, multiple recurrences in the remnant liver and peritoneal dissemination occurred. The patient underwent follow-up without adjuvant therapy and was well for more than 10 years after liver metastases and peritoneal dissemination after the initial surgery. This case represents the different biological behavior of pediatric gastrointestinal leiomyosarcoma compared to adult gastrointestinal leiomyosarcoma.

Abstract 299: Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers

Abstract Depending upon the definition used, as many as half of all cancers diagnosed are considered rare cancers, and most rare cancer patients would greatly benefit from additional therapies. Repurposing of drugs for use in oncology represents an attractive strategy for the rapid development of therapies that address the significant unmet medical need that remains for rare cancers. The FDA-approved anti-helminthic drug mebendazole (MBZ) has been reported to affect several biological pathways involved in tumor growth and metastasis. Based on this activity, multiple rare cancer tumor cell lines including neuroblastoma, carcinoid tumors, esophageal adenocarcinoma, gastrointestinal stromal tumors, leiomyosarcoma, pheochromocytoma, and mesothelioma were analyzed for their susceptibility to MBZ treatment alone or in combination with standard chemotherapeutic agents in vitro. Cultured cells exposed to increasing concentrations of MBZ alone showed a significant decrease in cell viability with IC50s ranging from 0.09-2.2 μM. To evaluate efficacy of MBZ in an additional model system, an ex vivo 3D assay using gastric cancer primary cells isolated from two patient-derived xenograft (PDX) models was performed. Cells were seeded in 3D cultures and treated for seven days with MBZ at nine different doses in triplicate. IC50s were determined to be 0.74 and 0.76 μM indicative of significant potency. These results along with the in vitro data generated using cell lines suggest that MBZ may represent an effective anti-cancer agent across multiple rare cancer indications. However, since tumor cells can often evade or develop resistance to single agent therapy, the potential for synergistic combinations with chemotherapeutic agents was also explored in vitro. Cells were plated in triplicate and treated with a range of concentrations of MBZ and relevant chemotherapeutic agents in a complete Latin square. Combination indexes (CI) were determined based on the method described by Chou and Talalay. Several synergistic drug combinations were identified with CI values ranging from 0.008 to 0.428 (CI < 0.9 indicates synergy). Overall, our results indicate that synergistic combinations of MBZ and chemotherapy agents represent a promising strategy for the treatment of rare cancers. Citation Format: Mahta Samizadeh, Debashree Chakrabarti, Yuhan Zhu, Robert Louis Treuting, Johanne Kaplan, William Siders, Jamie D. Barber. Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 299.

Ulcerated duodenal gastrointestinal stromal tumor – Demonstration of an interesting radiological sign (the Torricelli-Bernoulli sign)

The Torricelli-Bernoulli sign is a useful computed tomographic sign seen in ulcerated/necrotic gastrointestinal stromal tumor (GIST) or leiomyosarcoma characterized by the collection of air in the nondependent aspect of larger gastrointestinal cavitating tumors. This sign is based on the physical principle of the law of Torricelli's and Bernoulli's principle. Herein, we describe this interesting imaging sign in an adult male with malignant duodenal GIST with extensive hepatic, peritoneal, omental, and lymph nodes (though rare in GIST) metastasis. The patient succumbed few days after admission.

Presence of intermediate filament protein synemin in select sarcomas

Synemin, a large intermediate filament protein, is expressed during development in the central and peripheral nervous system as well as in tumors derived from those tissues. It is also abundant in all three types of muscle and more recently has been found in bone. The purpose of this study was to determine whether synemin is present in tumors of soft tissue and myogenic origin, and to semi-quantitate the amount of synemin therein. Using formalin-fixed, paraffin-embedded tissues, it was determined using immunohistochemistry that synemin was present in most sarcomas but was in highest quantities in gastrointestinal stromal cell tumors (GIST) and leiomyosarcomas. Synemin presence in leiomyosarcomas was not unexpected as it is already known to be found in benign smooth muscle. The presence of synemin in GIST was unexpected and may warrant follow up as a diagnostic marker.

Primary Gastric Leiomyosarcoma: A Rare Entity

Introduction: In the post c-KIT era, true smooth muscle neoplasms of GI tract have received little attention and are an extremely rare tumor. Here we report a case of primary gastric leiomyosarcoma (LMS) in an adult presenting with anemia. Case Report: A 54-year-old Caucasian male with past medical history of interstitial lung disease presented to the hospital for evaluation of lighheadness and multiple episodes of black tarry stool. On examination, patient's stool was guaiac positive with positive orthostatic vital signs. Patient underwent EGD which revealed a 3 cm bull's eye lesion in mid-gastric body with central depression (Fig 1). Endoscopic ultrasound showed a16 mm hypoechoic lesion in mid-gastric body, appeared to be arising from muscularis propria without any lymphadenopathy. Pathologic examination classified the tumor as LMS grade 2 of 3 based on immunohistochemical staining (negative c-Kit and DOG-1, positive desmin and actin), confirmed by 2 pathologists at different institutions (Fig 2). Patient underwent computed tomography and PET scan, which was negative for any metastasis and showed only positive uptake in mid-gastric body. On repeat EGD, his lesion has grown in size to 3 cm and appeared to invade serosa. At that point, surgical resection was undertaken and patient underwent partial gastrectomy with frozen section showing clear margins. The patient had uneventful recovery.Figure: EGD showing Bull'e eye like lesion in mid-gastric body.Figure: Immunohistochemical staining showing positivity for Actin (A), Desmin (B) in sheets of spindle cell (C).Discussion: LMS of the gastrointestinal (GI) tract are rare entity in the post-GIST era since c-kit was described in 1998 representing only 1% of true smooth muscle neoplasm of the GI tract. There are approximately 100 reported cases of GI LMS, with small intestine being the commonest site and stomach being the least common site. There are only 10 reported cases of gastric leiomyosarcoma in post-GIST era. The median age of gastric LMS is 37 years with males (70%) more commonly affected than females (30%). The most common reported symptom was GI bleeding, followed by abdominal pain, weight loss, and gastroesophageal reflux. The mean tumor size is 6.45 cm +/- 3. GISTs are positive for CD-117 and CD-34, which are negative in LMS. Moreover, LMS are positive for vimentin, smooth muscle actin and desmin. There is no consensus on treatment of LMS as they are rarely encountered. Our patient's LMS grew from 16mm to 30 mm within a month, demonstrating the aggressiveness of the tumor. Complete surgical resection with negative margins remains the gold standard treatment.

Transanal total mesorectal excision for a large leiomyosarcoma at the lower rectum: a case report and literature review

BackgroundRectal leiomyosarcoma (LMS) is an extremely rare disease. Previously, LMS was not properly distinguishable from gastrointestinal stromal tumor (GIST) until c-kit, a characteristic marker of GIST, was discovered in 1998. No standard therapeutic strategy for gastrointestinal LMS has been established except for surgical resection because of its rarity. Rectal LMS is often accompanied by symptoms, which can enable detection at a small size. However, when a large LMS is detected at the lower rectum, it is difficult to excise due to the narrow pelvic space.Case presentationWe present the case of an 86-year-old man with a large LMS. The LMS was asymptomatic and incidentally found at the lower rectum when he visited another hospital for management of benign prostatic hypertrophy. An abdominoperineal resection of the rectum was performed with combined resection of both seminal vesicles and a part of the prostate because tumor invasion was suspected. We used the hybrid method of laparoscopic and transanal total mesorectal excision (TaTME) approaches to achieve negative surgical margins. Late-onset urethral injury occurred in the postoperative course, which was successfully treated with a urethral catheter. The patient was discharged and received no adjuvant therapy. Local recurrence did not occur, but multiple lung metastases were detected 4 months later and the patient died 12 months after the surgery.ConclusionsThis is the first report of the hybrid method of laparoscopic and TaTME approaches to remove a large LMS at the lower rectum.

Curative resection for leiomyosarcoma of the descending mesocolon with metachronous liver metastasis: A case report and literature review.

Mesenteric leiomyosarcoma is a rare disease with poor prognosis. Previously, mesenteric leiomyosarcoma was not differentiated from gastrointestinal stromal tumor (GIST), which is the most common mesenchymal tumor of the gastrointestinal tract, and several cases of GIST may have been misclassified as mesenteric leiomyosarcoma. Thus, the actual clinicopathological characteristics of mesenteric leiomyosarcomas remain unclear. We herein describe a case of leiomyosarcoma arising in the descending mesocolon in a patient who developed metachronous liver metastasis. A 76-year-old woman reported a mass in her left upper abdomen. Computed tomography imaging revealed a low-density tumor adjacent to the descending colon. The patient underwent surgery and the tumor was resected along with part of the descending colon. Immunohistochemical differential diagnosis revealed that the tumor was positive for smooth muscle actin and desmin, and negative for CD117 (c-KIT) and S-100, which are characteristic of gastrointestinal leiomyosarcoma. A single liver metastasis developed 24 months after the operation. The patient underwent curative resection of the metastatic lesion. Sixteen months following surgery for the liver metastasis and 40 months after the initial removal of the primary lesion, the patient remains disease-free. The prognosis of leiomyosarcoma remains poor and standardized chemotherapy for this rare disease has not yet been established. Early diagnosis and surgical removal of the tumor is the only potentially curative option for liver metastasis of mesenteric leiomyosarcoma.

Synthesis and Cytotoxic Activity of Ethyl 2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)- 4,5-Dihydro-1H-Pyrrole-3-Carboxylates

Recyclization of 5-aryl-2,3-dihydro-2-furandione 3-benzoylhydrazones (I) induced by cyanoacetic ester produced ethyl 2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylates (IIa-g). The biological activity of the synthesized compounds, which possessed low toxicities, was investigated. Ethyl 2-amino-1-benzamido-5-[2-(4-chlorophenyl)-2-oxoethylidene]-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (IIf) and the 5-[2-(3,4-dimethoxyphenyl)-2-oxoethylidene] analog (IIc) exhibited the greatest cytotoxicities against several connective-tissue tumor cell lines, namely, gastrointestinal stromal tumors (GISTs), osteosarcoma U2OS, and leiomyosarcoma SK-LMS-1. Ethyl 2-amino-1-benzamido-4-oxo-5-[2-oxo-2-(p-tolyl)ethylidene]-4,5-dihydro-1H-pyrrole-3-carboxylate (IIa) suppressed significantly tumor growth of GIST, LMS, and OS cell lines. Its activity against GIST cells at 10 μM was comparable with that of imatinib (1 μM) and, at lower concentrations (2.5 and 5 μM), with those of doxorubicin (0.25 μg/mL) and etoposide (40 μM), and exceeded significantly those of taxol (1 μM) and hydroxyurea (1 mM). The cytotoxicities of most of the studied compounds at 10 μM against SK-LMS-1 and U2OS cells in vitro were significantly greater than all reference drugs (doxorubicin, taxol, etoposide, etc.).

Gastrointestinal (GI) leiomyosarcoma (LMS) case series and review on diagnosis, management, and prognosis.

This review of 76 gastrointestinal (GI) leiomyosarcoma (LMS) cases that include 11 cases from the American University of Beirut Medical Center represents, to our knowledge, the largest number of combined GI LMS cases reported. The age range of GI LMS is variable, and the presentation is non-specific, making pathological diagnosis essential. LMSs usually lack CD117 and CD 34 mutations and are usually positive for smooth muscle cell markers. The review highlights surgery as the mainstay of treatment with negative margins attained most of the times. Adjuvant chemotherapy is used in around 7-27% of the cases mainly for small intestinal and colorectal LMS. The relatively small number of patients is a limitation on outcome analysis. However, LMS has a risk of recurrence reaching 39-80% and secondary metastasis reaching 55-71% in small intestinal and colorectal cases. In light of the high frequency of recurrence and metastasis, enrolling patients in clinical randomized trials to investigate the role of chemotherapy, radiation therapy, and targeted therapy is required for better control of this rare aggressive GI tumor.

First case of intestinal leiomyosarcoma in a bearded dragon: Ultrasonographic findings

The paper presents a case of leiomyosarcoma of the gastrointestinal tract in a bearded dragon (Pogona vitticeps) with an ultrasound and histopathological description of pathological changes. According to our knowledge, leiomyosarcoma of the gastrointestinal tract and its ultrasound features have not been reported in lizards yet. A male bearded dragon (Pogona vitticeps), aged 4 years, was referred for radiological and ultrasound examination with a history of apathy and loss of appetite. A preliminary diagnosis of an advanced neoplasia process in the caudal coelomic cavity was established by diagnostic imaging methods. The owner decided to euthanize the animal and agreed to a post-mortem examination. After euthanasia, a histopathological examination was performed. In a radiological examination, an irregularly marginated radiopacity measuring 5.8 x 4.0 cm was visible in the central part of the coelom. Serosal margin details in the coelomic cavity were decreased, and differentiation of coelomic organs was impossible. An ultrasound examination confirmed a large amount of free echogenic fluid in the coelomic cavity. The liver had increased echogenicity, and a hypoechoic focal lesion was found in the right lobe. Mixed echogenicity masses were visible in the caudal coelom adjacent to the small intestinal loops. In one of the adjacent intestinal loops, a focal thickening of the small intestinal wall was observed with loss of the normal layered architecture. The mass had complex and mostly low echogenicity with a cystic lesion present in the centre. Necropsy confirmed the presence of proliferative lesions in the body cavity, originating from the intestine and infiltrating the mesentery and the lumbar spine area as well as the gonads located at this site. On the basis of the histological structure of the intestinal tumour, the neoplastic proliferation was classified, according to the WHO classification, to a group of malignant tumours with characteristics of leiomyosarcoma and arising from the smooth muscles. The ultrasonographic features of gastrointestinal leiomyosarcoma in that lizard corresponded to features found in dogs, in which such tumours occur as eccentric, poorly echogenic masses with anechoic cavities in large changes. Leiomyosarcoma in reptiles can be locally invasive as well. Metastatic foci are also possible, especially in the liver.

Abstract 1572: Dystrophin Is a tumor suppressor in human cancers with myogenic programs

Abstract Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation. Although presumptive initiating mutations have been identified in these cancers, the subsequent mechanisms of malignant progression are not known. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Genome-wide SNP screens demonstrated DMD intragenic deletions in 23 of 38 myogenic sarcomas (61%) compared to 0 of 58 non-myogenic sarcomas (p < 0.0001). Although DMD is an X-linked gene, somatic DMD deletions affected both sexes equally and DMD deletions in female patients involved the active X chromosome, resulting in functional DMD nullisomy. Dystrophin was expressed strongly in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions in the malignant myogenic sarcomas clustered at the 5′ end of the gene, inactivating larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform (Dp71) which is encoded by the DMD 3′ end. Dystrophin restoration inhibited myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. The genomic, clinicopathological and functional evidence validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer. Citation Format: Yuexiang Wang, Adrian Marino-Enriquez, Richard Bennett, Meijun Zhu, Grant Eilers, Cristina Antonescu, Christopher Fletche, Chandrajit Raut, Matt van de Rijn, Louis Kunkel, George Demetri, Jonathan Fletcher. Dystrophin Is a tumor suppressor in human cancers with myogenic programs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1572. doi:10.1158/1538-7445.AM2014-1572

MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours

Background:Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool.Methods:Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs.Results:MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and – to a lesser extent – mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively.Conclusion:MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.